title: Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy.
abstract: Histone deacetylase (HDAC) inhibitors (HDACis) are well-characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome-associated myeloid leukemia (DS-AMKL) blasts. Investigating the antileukemic function of HDACis revealed their transcriptional and post-translational regulation of key autophagic proteins, including ATG7. This leads to suppression of autophagy, a lysosomal degradation process that can protect cells against damaged or unnecessary organelles and protein aggregates. DS-AMKL cells exhibit low baseline autophagy due to mammalian target of rapamycin (mTOR) activation. Consequently, HDAC inhibition repressed autophagy below a critical threshold, which resulted in accumulation of mitochondria, production of reactive oxygen species, DNA damage and apoptosis. Those HDACi-mediated effects could be reverted upon autophagy activation or aggravated upon further pharmacological or genetic inhibition. Our findings were further extended to other major acute myeloid leukemia subgroups with low basal level autophagy. The constitutive suppression of autophagy due to mTOR activation represents an inherent difference between cancer and normal cells. Thus, via autophagy suppression, HDACis deprive cells of an essential pro-survival mechanism, which translates into an attractive strategy to specifically target cancer cells.
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
authors.forename: M V
authors.initials: MV
authors.lastname: Stankov
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: El Khatib
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Kumar Thakur
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Heitmann
authors.affiliation: Section of Molecular Dermatology, Department of Dermatology, Venerology and Allergology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Panayotova-Dimitrova
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schoening
authors.affiliation: Division of Pediatric Oncology, Universitäts-Kinderklinik Zurich, Zurich, Switzerland.
authors.forename: J P
authors.initials: JP
authors.lastname: Bourquin
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School, Hannover, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Schweitzer
authors.affiliation: Section of Molecular Dermatology, Department of Dermatology, Venerology and Allergology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Leverkus
authors.affiliation: Department of Molecular Hematopoiesis, Hannover Medical School, Hannover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Welte
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Reinhardt
authors.affiliation: Division of Genetics, Brigham & Women's Hospital, Boston, MA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: 1] Harvard Medical School and Harvard Stem Cell Institute, Boston, MA, USA [2] Department of Pediatric Oncology, Dana Farber Cancer Institute and Children's Hospital, Boston, MA, USA [3] Howard Hughes Medical Institute, Boston, MA, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
authors.forename: G M N
authors.initials: GM
authors.lastname: Behrens
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: J H
authors.identifier: 0000000210700727
authors.initials: JH
authors.lastname: Klusmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D017382:Reactive Oxygen Species